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The regulation of JAKs in cytokine signaling and its breakdown in disease

机译：在细胞因子信号传导中的jaks调节及其疾病分解

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The JAK-STAT signal transduction pathway is responsible for mediating signals of over fifty cytokines, growth factors and hormones. Signaling through the JAK-STAT pathway is regulated on multiple levels, including intramolecular regulation by the JAK pseudokinase domain, and intermolecular regulation by a host of regulatory proteins. The advent of accessible genomic tools have provided a wealth of information on disease-associated mutations in the JAK-STAT pathway and its regulatory components. The vast number of these mutations in diseases ranging from immunodeficiencies and obesity to many cancers highlight the importance of correct regulation of JAK-STAT signaling for biological processes such as hematopoiesis, regulation of the immune system, metabolism, and growth. Simultaneously, JAK inhibitors are gaining traction in clinical use, both for treatment of diseases driven by JAK mutations, and for a host of inflammatory disorders, in which proin-flammatory cytokine signaling through the JAK-STAT pathway is an integral part of pathogenesis. The elucidation of molecular mechanisms in the pathogenesis of complex diseases has also, however, brought the limitations of our current understanding on the regulation of cytokine signaling to the foreground. Indeed, deeper understanding of these regulatory mechanisms are a prerequisite for the development of the next generation of pharmacological modulators of the JAK-STAT pathway. In this review we discuss the current state of knowledge of the intra- and intermolecular regulation of the JAK-STAT pathway, with a focus on diseases arising from disruptions in the regulatory apparatus.
机译：Jak-Stat信号转导途径负责介导超过五十个细胞因子，生长因子和激素的信号。通过JAK-STAT途径的信号传导在多个水平上调节，包括JAK伪转基因酶结构域的分子内调节，并通过一系列调节蛋白进行分子间调节。无障碍基因组工具的出现提供了有关JAK-STAT途径及其监管组分中的有关疾病相关突变的大量信息。疾病中大量这些突变从免疫缺乏和肥胖到许多癌症的重要性突出了诸如造血，免疫系统的调控等生物过程的正确调节Jak-Stat信号传导的重要性，免疫系统，新陈代谢和生长。同时，JAK抑制剂在临床用途中获得牵引力，用于治疗由JAK突变驱动的疾病，以及用于致炎症紊乱的疾病，其中通过JAK-STAT途径的促进细胞因子信号是发病机制的组成部分。然而，阐明了复杂疾病发病机制中的分子机制也使我们目前对前景中细胞因子信号调节的了解的局限性。事实上，对这些监管机制的更深层次的了解是开发Jak-Stat途径的下一代药理调节剂的先决条件。在本文中，我们讨论了JAK-STAT途径的内分分子和分子间调节的现状，重点是监管设备中断所引起的疾病。

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